A Prospective Study Comparing Functional Imaging (18F-FDG PET) Versus Anatomical Imaging (Contrast Enhanced CT) in Dosimetric Planning for Non-small Cell Lung Cancer

Objective(s): 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET-CT) is a well-used and established technique for lung cancer staging. Radiation therapy requires accurate target volume delineation, which is difficult in most cases due to coexisting atelectasis. The present study was performed to compare the 18F-FDG PET-CT with contrast enhanced computed tomography (CECT) in target volume delineation and investigate their impacts on radiotherapy planning. Methods: Eighteen patients were subjected to 18F- FDG PET-CT and CECT in the same position. Subsequently, the target volumes were separately delineated on both image sets. In addition, the normal organ doses were compared and evaluated. Results: The comparison of the primary gross tumour volume (GTV) between the 18F-FDG PET-CT and CECT imaging revealed that 88.9% (16/18) of the patients had a quantitative change on the 18F-FDG PET-CT. Out of these patients, 77% (14/18) of the cases had a decrease in volume, while 11% (2/18) of them had an increase in volume on the 18F-FDG PET-CT. Additionally, 44.4% (8/18) of the patients showed a decrease by > 50 cm3 on the 18F-FDG PET-CT. The comparison of the GTV lymph node between the 18F-FDG PET-CT and CECT revealed that the volume changed in 89% (16/18) of the patients: it decreased and increased in 50% (9/18) and 39% (7/18) on the 18F-FDG PET-CT. New nodes were identified in 27% (5/18) of the patients on the 18F-FDG PET-CT. The decrease in the GTV lymph node on the 18F-FDG PET-CT was statistically significant. The decreased target volumes made radiotherapy planning easier with improved sparing of normal tissues. Conclusion: GTV may either increase or decrease with the 18F-FDG PET-CT, compared to the CECT. However, the 18F-FDG PET-CT-based contouring facilitates the accurate delineation of tumour volumes, especially at margins, and detection of new lymph node volumes. The non-FDG avid nodes can be omitted to avoid elective nodal irradiation, which can spare the organs at risk and improve accurate staging and treatment.

10-12% of cancer patients have lung cancer, which is the most common cancer among males (1). Based on the hospital-based cancer registries, the lung cancer is one of the top three and top ten cancers among males and females, respectively (2). Surgery is the treatment of choice for medically fit patients with early-stage lung cancer. Nevertheless, medically inoperable stages I, II, and III lung cancers are primarily treated by radiotherapy (RT) either with or without chemotherapy (3). In many studies, five-year survival for patients with stage I disease exceeded 60%; however, in stage III disease, it varied around 15% (4,5).
The locoregional control of lung cancer, achieved either by surgery and/or chemoradiotherapy, plays an important role in the treatment of this cancer, which in turn may contribute to better survival. Therefore, it is frequently emphasized that better RT techniques are needed to provide improved targeting of the tumour and optimally spare the adjacent normal tissues and uninvolved lung. However, it is essential to accurately identify tumour volumes in order to have improved RT techniques. The goal is to prevent missing marginal tumour tissue, which highlights the importance of better imaging for volume delineation.
Traditionally, the target volumes are delineated on computed tomography (CT) images with fusion of magnetic resonance imaging (MRI) when available. Nevertheless, the lung MRI is not used due to artefacts caused by respiratory motion. Lung tumours, especially squamous cell tumours, are more commonly located centrally and cause atelectasis, which is difficult to differentiate from the tumour itself on the planning CT images. This leads to large target volumes with increased radiation toxicity. Additionally, relatively large mediastinal nodes may not actually harbour metastasis, and if they are included in the target volume, it may lead to increased toxicity. Therefore, functional imaging such as 18 Fluorine-labelled fluorodeoxyglucose positron emission tomography co-registered with computed tomography ( 18 F-FDG PET-CT) may facilitate the delineation (4). Apart from volume delineation, the 18 F-FDG PET-CT is proven to accurately stage the disease and improve the treatment decision making.
Therefore, this study was undertaken in order to investigate the impact of functional imaging on target volume delineation and RT planning. To this aim, we compared the functional imaging (i.e., 18 F-FDG PET-CT) with anatomical imaging (i.e., contrast enhanced computed tomography [CECT]) in the gross tumour volume (GTV) delineation of non-small cell lung cancer (NSCLC). Additionally, dosimetric measurements were taken of the adjacent organs at risk (OAR) in the RT treatment planning of NSCLC.

Methods
This prospective study was conducted on 40 NSCLC patients during April 2014-July 2015 in a tertiary care hospital after obtaining approval from the Institutional Ethics Committee. The NSCLC patients, diagnosed via histopathology, were subjected to 18 F-FDG PET-CT in the treatment position, i.e., supine with hands above the head with three reproducible fiducial markers. If proven to be non-metastatic (18 patients), a planning CECT was performed in the treatment position.
The 18 F-FDG PET-CT and CT imaging (3-mm slices) were implemented during quiet breathing from the base of the skull through the proximal thighs at 110 kVp and 70-110 mA. The PET images were obtained over the same anatomic extent beginning 45-60 min after the administration of 0.2 mCi/kg bodyweight (BW) of 18 F-FDG. Accordingly, 8-10 bed positions were imaged per patient, depending on the patient height with imaging times of 2-4 min per bed position.
Subsequently, within one week, a planning CECT (Somatom Definition AS 16-slice multidetector, Siemens, Germany) was performed in the treatment position with intravenous administration of nonionic contrast at 1-2 mL/kg of BW. The CT images (3-mm slices) were typically obtained during quiet breathing from the chin to the umbilicus at 110 kVp and 70-100 mA.
The 18 F-FDG PET-CT and planning CECT images were imported to the Eclipse treatment planning system version 2007. Then, the target volumes were contoured according to the international commission on radiological units and measurements (ICRU) report 50. Contouring was performed on the CECT images without utilising the 18 F-FDG PET-CT images to avoid bias.

Contouring on CECT
The GTV contouring was performed for the primary tumour and lymph nodes. The primary tumour was outlined using both lung window settings (W=1,600, C=600) and mediastinal window settings (W=400, C=40) to optimise the definition at the interfaces with normal structures. Bone windows were used if the tumour abutted or involved the bone (W=1,600, C=400). Furthermore, the lymph nodes were defined using the mediastinal windows. An involved lymph node was defined as having a size of more than 1 cm on the short-axis diameter. The CECT-GTV encompassed the GTV of primary tumour and lymph node. The clinical target volume (CTV) was contoured on the CECT by a AOJNMB uniform outgrowth of the CECT-GTV by 1.5 cm, and the margin was reduced near critical structures like the spinal cord. The planning target volume (PTV) on the CECT was created by an isotropic outgrowth of a 5 mm margin circumferentially.

Contouring on 18 F-FDG PET-CT
The target volumes were contoured on the CT component of the 18 F-FDG PET-CT with the help of PET. The treating radiation oncologist and nuclear medicine physician determined the tumour delineation based on the 18 F-FDG PET-CT via visual interpretation. The window settings were adjusted with view parameter at hot iron mode, and mass with greater activity than mediastinal blood pool activity was contoured.
For the patients with a collapsed lung, the presence of 18 F-FDG-avid disease on the planning 18 F-FDG PET-CT scan was used to define an anatomic margin. The lymph nodes with 18 F-FDG uptake on the 18 F-FDG PET-CT scan were considered as positive.
The distinction between the benignappearing lymph nodes versus malignantappearing lymph nodes was based on a greater intensity of 18 F-FDG PET-CT uptake, compared to the mediastinal blood pool.
The PET-CT-based GTV encompassed the PET-CT-based GTV of the primary tumour and lymph nodes. The PET-CT-based CTV and PET-CT-based PTV were contoured in a similar way to the CECTbased CTV and CECT-based PTV. The delineated OAR were as follows: Lungs: automatically delineated on the Eclipse treatment planning workstation, and then manually modified to exclude the trachea and bronchi; Heart: delineated from the bottom of the aortic arch to the bottom of the heart; Spinal cord: delineated slice by slice after adjusting the CT window width and level to clearly demonstrate the spinal cord; Oesophagus: delineated from the level of the cricoid cartilage to the area above the oesophagogastric junction. The target volumes were planned with threedimensional conformal radiotherapy (3D-CRT). Accordingly, PTV received 95% of the target dose, and normal organ doses fell within the tolerance limits recommended by the Quantitative Analysis Of Normal Tissue Effects In The Clinic (QUANTEC). The study parameters, namely GTV (i.e., GTV of primary tumour and lymph nodes), mean lung dose (MLD), lung volume receiving more than 20 gray (V20), mean oesophageal dose (MED), mean heart dose (MHD), heart V30, and maximum spinal cord dose (MSD) were compared on CECT and 18 F-FDG PET-CT. The median values were derived and analyzed using the Mann-Whitney U test, which is a nonparametric statistical test, through the SPSS software version 20. The P-value less than 0.05 was considered statistically significant.

Results
Forty patients with histopathologically proven NSCLC during the study period were screened for inclusion into the study. Out of these patients, 14 cases were excluded from the study for several reasons including obvious metastatic disease, renal failure, and contrast allergy. After the exclusion, 26 patients were subjected to 18 F-FDG PET-CT in the treatment position. Eight patients were diagnosed with metastatic disease on the 18 F-FDG PET-CT; as a result, the treatment intent was changed from curative to palliative, and they were excluded. Finally, 18 patients were recruited into the study. These patients were subjected to planning CECT in the same position, and volumes were separately contoured and planned.

Stage migration
When the individual T, N, and M stages of each subject on the 18 F-FDG PET-CT imaging were compared to the CECT imaging, the following changes were identified on the 18 F-FDG PET-CT: Tumour status (T) was downstaged in 2/18 (11%) patients.
Out of the 18 participants, 17 were male. The age of presentation varied from 50-70 years with a mean age of 60.33 years. Pulmonary involvement was predominantly right-sided with a right to left ratio of 2:1. Stage-wise distribution showed that the majority of the patients (56%, 10/18) presented stage IIIA. Furthermore, site-wise distribution showed that most of the patients (62%, 11/18) had tumour in the upper lobe. Histopathologically, the majority of the patients (62%, 11/18) had an adenocarcinoma located peripherally in the lung. (Table 1) Out of the 18 patients, 16 cases showed a quantitative tumor volume change on the 18 F-FDG PET-CT, nevertheless, no volume change was  Figure 1). In addition, the GTV of primary tumor increased on the 18 F-FDG PET-CT in 11% (2/18) of the participants (Figure 2, 3). (Table 1) The GTV lymph node changed in 89% (16/18) of the patients on the 18 F-FDG PET-CT imaging. Out of these patients, 50% (9/18) and 39% (7/18) of the participants showed decrease (Figure 4, 5) and increase ( Figure 6) in the GTV lymph node, respectively. Furthermore, new nodes were identified in 27% (5/18) of the patients on the 18 F-FDG PET-CT imaging. However, two patients had no lymph node involvement on any imaging.

Impact on planning
Although there was a volume change on the 18 F-FDG PET-CT, the same RT plan, generated on the CT-based volumes, can have adequate coverage when used on the 18 F-FDG PET-CT-based volumes. However, if the coverage is suboptimal on the 18 F-FDG PET-CT, a new plan is generated. Accordingly, in the present study, we applied the same plan when dose coverage was suboptimal in 50% (9/18) of the patients and,  replanning was required.
In the present study, all OAR doses were within the tolerance limits. When the OAR impact was analysed, all the patients had an increase in such parameters as MLD, V20, MHD, V30, and MED as well as a decrease in the MSD  on the 18 F-FDG PET-CT-based plan ( Table 2, 3). However, the analysis of the data related to the patients with decreased GTV of primary tumor on the 18 F-FDG PET-CT revealed an increase in the OAR parameters including MLD, V20, MHD, V30, and MED and a decrease in the MSD due to the increase in the GTV lymph node volume ( Table 4, 5). Nevertheless, all OAR doses were within the normal limits.
In the present study, the analysis of the OAR impact among the patients with decreased GTV lymph node on the 18 F-FDG PET-CT indicated an increase in such OAR parameters as MHD and heart V30. Furthermore, this analysis showed a decrease in parameters like MLD, lung V20, MED, and MSD (Table 6, 7). However, there was a decrease in the GTV of primary tumor due   to the presence of a bulky disease in the lungs. Consequently, the plan was optimized towards sparing the lung given the history of chronic pulmonary disease in these patients.
On the other hand, the analysis of the OAR impact among the patients with increased GTV lymph node on the 18 F-FDG PET-CT revealed an  increase in the OAR parameters like MLD, V20, MHD, V30, MED, and MSD (Table 8, 9). However, there was a decrease in the GTV of primary tumor on the 18 F-FDG PET-CT due to an increase in the lymph node volume leading to a greater mediastinal area for treatment.

Discussion
Around 10-15% of the newly registered patients had carcinoma lung in the hospital under investigation. The primary treatment of the early stage lung cancer is either surgery or stereotactic body radiotherapy. However, for the locally advanced disease, the RT with concurrent chemotherapy is the treatment of choice. Local control is necessary for a longterm disease-free survival. There are some measures to improve the local control including optimum tumour coverage with radiation by improving tumour delineation, improving RT planning technique, and precise delivery of radiation to the tumour (4).
In the 3D-CRT planning, the GTV delineation should be accurate because if contour is underdrawn or overdrawn, it may lead to local recurrence or increased normal organ doses, respectively. The main drawback during tumour delineation is the identification of atelectasis and loculated pleural effusion at the tumour-normal lung interface. The addition of functional imaging like 18 F-FDG PET-CT clarifies tumour edges and simplifies delineation. If the target volume is relatively small and accurate, planning will be easy; therefore, the OAR will be spared, and even the dose escalation can be tried.
In our institute, we treat the locally advanced NSCLC patients with definitive radiation by 3D-CRT either with or without concurrent chemotherapy. We delineate target volumes based on the guidelines of the ICRU reports 50 and 62 on CECT imaging. Consequently, we compared the 18 F-FDG PET-CT-based target volumes with the CECT-based target volumes and their impacts on the OAR.

Impact on target volume delineation
In the 3D-CRT, the tumour volumes are delineated on the CT images. When the NSCLC patients have atelectasis or obstructive pneumonia, it is difficult to distinguish the boundaries between the incompletely expanded lung tissue and tumour tissue by conventional CT, which often results in inaccurate target delineation. Therefore, it leads to insufficient dose coverage of the target volume or too much damage to normal tissue.
According to the Radiation Therapy Oncology Group, the role of the elective lymph node irradiation is still an unresolved issue, and only involved nodes should be treated (5). The 18 F-FDG PET-CT can effectively identify the boundary between the atelectasis and lung cancer, making the radiation target area precise. Therefore, it improves the local control, avoids unnecessary radiation injury, and reduces the radiation complications (6).
Toloza et al. conducted a pooled analysis over the sensitivities and specificities of the CT and PET, compared to the pathological staging of the mediastinum. For the CT, the pooled sensitivity and specificity were 0.57 and 0.82, respectively. For the PET, the pooled sensitivity and specificity were 0.84 and 0.89, respectively (7). Therefore, to improve the target volume delineation, especially of the mediastinum, we used the 18 F-FDG PET-CT. In the present study, the 18 F-FDG PET-CT-based contours showed both increase and decrease in the volume, compared to the CECT.

Reason of the reduction in the GTV of primary tumour on 18 F-FDG PET-CT
As shown in Figure 1, due to the associated collapse of lung tissue distal to the bronchial obstruction, the tumour is not differentiated from the atelectasis, which resulted in increased volume. However, as shown in the 18 F-FDG PET-CT image, the 18 F-FDG avidity facilitated the accurate identification of tumour margins by differentiating the tumour from atelectasis and decreasing the GTV of primary tumour volume on the 18 F-FDG PET-CT-based contours.

Reason of the increase in the GTV of primary tumour on 18 F-FDG PET-CT
As illustrated in Figure 2, there is a high risk of marginal tumour miss due to the inability to accurately identify tumour margins near the chest wall and mediastinum. The 18 F-FDG PET-CT imaging allowed for accurate identification of the mediastinum and chest wall involvement, which facilitated accurate delineation; however, it increased the tumour volume on the 18 F-FDG PET-CT-based contours.

Reason of the reduction in the GTV lymph node on 18 F-FDG PET-CT
As presented in Figure 3, the mediastinal node greater than 1 cm in size on cross-section was considered involved and included in the GTV lymph node. However, the high negative predictive value of the 18 F-FDG PET-CT decreased the GTV

Conclusion
The PET-CT-based GTV may decrease or increase, compared to the CECT-based GTV. PET -CT-based contouring more accurately delineates tumour volumes (obstructive pneumonia and atelectasis), decreases contouring variability through more accurate tumour margins identification, and detects new lymph node volumes. Nodes, which are non-18 F-FDG avid on the PET-CT could be omitted to avoid elective nodal irradiation, which can spare adjacent OAR. It also facilitates the accurate staging and treatment.
However, definite statistical statements cannot be made due to the small sample size and dosimetric nature of this study. Further randomised trials with larger sample size and a longer duration of followup are required to reach a consensus.